"WILT (Whole-body Interdiction of Lengthening of Telomeres) as a truly un-escapeable anti-cancer therapy"
December 2nd, 2002 at the University of Cambridge, UK
Organizer: Aubrey de Grey
Click here to read the paper written by the participants.
Original Summary Text
On December 2nd, 2002, a roundtable meeting was held to discuss the long-term feasibility of a highly audacious approach to the prevention and cure of cancer.
The prospective therapy discussed is sufficiently outrageous that it merits a little justification before being described. The thinking behind it is as follows:
- Cancer has been popularly perceived as imminently curable, and has therefore received huge funding, for over 40 years; yet, there has not been all that much progress in actually reducing the age-specific death rate from cancer. This sustained overoptimism has, above all, been due to a widespread failure to appreciate the enormity of the power that a tumour obtains from its genomic instability and consequent ability to exploit natural selection to outflank both endogenous and therapeutic attempts to destroy it.
- Though this obstacle is now better understood, the main result has been a down-grading of what is thought of as "curing" cancer. It is now considered a cure if a cancer in a middle-aged or older person is staved off for a decade or so. This is justified, because in that time there is a fair chance of the person dying of some other age-related cause; hence, the chance of death from the cancer is markedly reduced.
- However, this situation may be short-lived. All other aspects of age-related degeneration and disease, including several that are at present just as immutable as the nastiest cancers, have recently been authoritatively stated to have a good chance of being comprehensively combated -- not just delayed by a decade or so -- with technology that could be developed in mice within a decade and in humans maybe not very long thereafter1,2. If this occurs, and unless progress against cancer is hugely more rapid in the next few decades than in the past few, cancer will be by far the leading cause of death thereafter.
It is thus reasonable to plan -- now -- for the unpleasant contingency that currently promising innovations in cancer therapy will fare little better than those of recent decades, and to design and evaluate options that are technologically a lot further away but should, if successful, combat cancer to the much greater extent foreseeable for other aspects of aging and age-related disease.
The specific strategy that this meeting examined is based on the following observations, for all of which there is good evidence:
- Virtually all hard-to-treat cancers in humans depend absolutely on the maintenance of telomere length through very large numbers of cell divisions. Without this, they cannot reach a life-threatening stage -- in particular, they cannot grow much after metastasis.
- Telomere maintenance is achieved by the action of only two known pathways: telomerase and ALT. The genes encoding the two subunits of telomerase are known; ALT has yet to be defined genetically, but good progress on doing so is being made.
- Our various stem cell pools need to divide considerably more often in a lifetime than they could without telomere maintenance, and they indeed express telomerase (though none has been reported to express ALT). Genetic defects in telomere maintenance result in dyskeratosis congenita (DC), a family of diseases characterised by deterioration of rapidly-renewing tissues.
- Dysfunctionally short telomeres actually promote cancer, both in DC and in late-generation telomerase knockout mice. This may be because of a residual telomere maintenance capacity stimulated by the genomic instability that having short telomeres confers.
- The mean age of onset of DC is around ten years. Hence, permanent abolition of telomere elongation -- throughout the body -- might have no serious side-effects for about a decade, except on male fertility. This is not certain, because all known mutations causing DC, or even its severe allelic variant Hoyeraal-Hreidarsson syndrome, may retain some telomere elongation activity. Conversely, however, it may be an underestimate, since cell division is faster in the fetus and neonate than in the adult and since the gene most often mutated in DC, DKC1, seems to have a nucleolar as well as telomeric function. At any rate, the division frequency of the fastest-dividing stem cells of the mouse, those in the gut3, is estimated to be 5000 over a lifetime in humans4, which over ten years equates to not much more than the 450 achieved by telomerase-negative mouse ES cells before they resort to an ALT-like pathway5.
- The rate of progress in stem cell research gives cause for optimism that within a couple of decades we will have very comprehensive ability to culture and reprogram cells ex vivo, so as to generate stem cells of any desired cell type in essentially unlimited quantity. This scenario is of course by no means assured, but it is likely enough to justify thinking now about how it might be exploited.
These observations appear, in theory, to suggest that life-threatening cancer progression could be indefinitely avoided by the roughly decadal reseeding of all our stem cell pools with autologous ones that had been engineered ex vivo to lack the genes for telomerase or ALT, but to have long telomeres. Such cells could potentially give rise to cancers -- especially when they became functionally impaired by short telomere length -- but the progression of such cancers would be minimal because no telomere elongation system could be activated even by hypermutation. Instead, once their telomeres became inadequate these cells would tend to differentiate, thereby having no functional effect on their tissue except for the depletion of stem cell numbers, which would be reversed by the next reseeding. Cells naturally present in the body could still potentially activate telomerase or ALT, but they would be progressively eliminated by dilution with the engineered cells, and they could also be more aggressively "defused" by homologous recombination-based gene therapy (introducing nonsense mutations in the relevant genes in situ) and/or by chemotherapy with agents to which the engineered stem cells had been made resistant. (Homologous recombination would presumably be preferred in the case of more slowly-renewing tissues, whose stem cells should not need reseeding.) Hence, one's risk of cancer would actually decline with age.
In this roundtable, we discussed the plethora of possible obstacles to the feasibility and development (even on a multi-decade timescale) of such therapy. Questions addressed included the following:
- Do cancers always regress before killing us if they can't maintain their telomeres?
- Can telomere maintenance be eliminated effectively (and selectively) enough by more tractable approaches?
- Can telomerase and ALT both be eliminated without deleterious effects on the cell or tissue that are independent of telomere length?
- Is ALT+ a simple loss-of-function mutation (which might be harder to engineer un-activatability of)?
- Are all stem cell pools easy enough to repopulate? The bone marrow seems simple, but is it? What about the gut? Skin? Lung? Others?
- Can we rely on telomere-depleted stem cells removing themselves by differentiation? If not, what strategies are appropriate to prevent deleterious side-effects?
- What influences the age of onset of DC, and can this be modulated genetically? What is the typical rate of telomere elongation in DC as a proportion of wild-type?
- How long can human telomeres be made and still work? Will their rate of attrition when very long be as slow as seen in telomerase-negative mouse cells? If not, how might it be slowed to that rate?
In order to address this wide range of topics as knowledgeably as possible, the participants in this roundtable comprised leading experts in all the relevant areas. The participants and their fields of expertise were:
Aubrey de Grey - Chair
Steven Artandi - Telomerase-negative mice
Charles Campbell - Gut stem cells and their transplantation
Inderjeet Dokal - Dyskeratosis congenita
Leslie Fairbairn - Cancer chemotherapy; manipulating resistance
Gerry Graham - Bone marrow transplants; long-term potency
Colin Jahoda - Skin stem cells and their transplantation
Andrew Porter - Homologous recombination-based gene therapy
Nicola Royle - ALT (Alternative Lengthening of Telomeres)