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SENS roundtable 3: WILT (Whole-body Interdiction of Lengthening of
Telomeres) as a truly un-escapeable anti-cancer therapy Roundtable
meeting, Cambridge, UK, December 2nd 2002 SENS圆桌会议 3：阻断全身端粒加长（WILT）作为一种真正不可避免的抗癌疗法 圆桌会议，剑桥，英国，2002年12月2日 文章（Article） 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. 2002年12月2日，举行了一次圆桌会议，讨论一种极其大胆的预防和治愈癌症途径的长期可行性。 The
prospective therapy discussed is sufficiently outrageous that it merits a
little justification before being described. The thinking behind it is as
follows: 所讨论的预想疗法十分离经叛道，在被描述之前，大为不合常理。 1) 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. 1）癌症普遍被认为很快可治愈疾病，因此，40多年来得到大量资助，但实际上在减少年龄特异的癌症死亡率方面并没有多少进展。这种持续的盲目乐观，首先是由于没有认识到，肿瘤从它的基因组不稳定性所获得的的巨大能力，能够利用自然选择战胜要毁坏它的内部的和治疗的尝试。 2) 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. 2) 虽然这一障碍现在有了较多的了解，但是，认为能“治愈”癌症的主要效果还是不行。现在正是我们来考虑中老年人中一种癌症能否被阻挡10年左右的疗法。这是合理的，因为此时这些人死于某些其它关龄原因的机会大增，因此，死于癌症的机会大减。 3) 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 thereafter [Annals NY Acad Sci 959:452-462; BioEssays
24:667-676]. 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. 3）然而，这种情形可能不会持续很长时间。关龄退行性变化和疾病的所有方面，包括几种现在还是像最讨厌的癌症那样永恒的疾病，目前都被权威地声称有全面地被抗击的很好机会――时间只在10年左右――其技术能够在10年中在小鼠中被开发出来，然后很快地轮到人类[Annals NY Acad Sci 959:452-462;
BioEssays 24:667-676]。果真如此，除非抗癌进展在下一个几十年比前几十年大大提速，否则癌症还会像现在是那以后的头一位死因。 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. 这样，现在正是有理由为不愉快的可能性作个筹划的时候了：当前看好的癌症疗法革新，比近几十年的那些，也好不了哪里去，现在该是设计和评估这样的选择：它们在技术上还没达到，但如果成功，抗癌将被推进到高得多的高度，这可从老化和关龄疾病的其它方面预见到。 The specific
strategy that this meeting examined is based on the following observations,
for all of which there is good evidence: 这次会议所检查的特殊战略，它所依据的所有观察都有很好的证据。 a) 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. a) 事实上，人类所有难治的癌症，都是绝对依赖于通过很多次细胞分裂还能维持端粒长度。若无此，则它们不可能达到威胁生命的阶段――特别是在转移之后它们不可能生长很多。 b) 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. b) 端粒维持只有两条已知的途径起作用：端粒酶和ALT。编码端粒酶两个亚单位的基因是已知的；ALT在遗传上有待详细说明，但是这方面正在取得很好进展。[译者注：ALT 是“端粒的替代性加长”
(alternative lengthening of telomeres)的英文缩写，意指在缺乏端粒酶活性的细胞中，端粒也能被某种机制所加长。] c) 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. c)我们各种干细胞库都需要终生分裂，分裂频度大大超过若无端粒维持它们就不能够的程度，它们确实表达端粒酶（虽然还没有表达ALT的报告）。端粒维持的遗传缺陷导致角质化不良症（dyskeratosis congenita ，DC），这是一组疾病，特征是迅速更新组织的退行性变化。 d)
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. d) 功能不全的短端粒实际上还会促进癌症，这在DC中是这样，在后代端粒酶敲除小鼠中也是这样。这可能是由于残余的端粒维持能力被基因组不稳定性（赋予短的端粒）所刺激。 e) 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 gut [J Cell Sci Suppl. 10:45-62], is
estimated to be 5000 over a lifetime in humans [BioEssays 24:91-98], 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 pathway
[Mol Cell Biol 20:4115-4127]. e) DC发作的平均年龄是10岁左右。因此，全身端粒加长的永久废除大约10年内没有什么严重副作用（雄性生殖力除外）。这不是很肯定，因为引起DC的所有已知突变、或甚至严重的等位基因变异Hoyeraal-Hreidarsson综合症，可能仍然有某些端粒延长活性。然而，相反地，（10年）可能是一种低估，因为在胎儿和婴儿中，细胞分裂快于在成人中，还因为在DC、 DKC1中经常突变的基因，似乎有核仁和端粒的功能。无论如何，在小鼠肠子中[J Cell Sci Suppl. 10:45-62]分裂最快的干细胞的分裂次数，在人类一生中估计分裂5000次[BioEssays 24:91-98]， 10年时间被端粒酶负鼠ES细胞所达到的分裂次数，在它们采取类ALT通路之前，不超过450次[Mol Cell Biol 20:4115-4127].。 f) 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. f) 干细胞研究进展速度使我们有理由乐观：在20年内我们将有非常普遍的能力在体外培养和重新编程细胞，以至于能无限量地产生任何类型我们想要的干细胞。当然，这种情景还不能确定，但是，现在就可以足够合理地考虑它的应用。 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. 在理论上，这些观察显然提示了，威胁生命的癌症进展可以被无限期地避免，办法是大约10年就用自身干细胞来种植一次我们的全部干细胞库――这些自身干细胞已在体外经过加工，使其缺乏端粒酶基因或ALT基因、但有很长的端粒。这样的细胞可能潜在地会长癌（特别是因端粒短而使它们的功能受到削弱），但这样的癌症进展是微不足道的，因为没有端粒延长系统可以被激活（哪怕是高突变率也不能激活）。一旦它们的端粒不合适，这些细胞就会倾向于分化，因此，就不会对它们的组织有功能效应，除非干细胞数目耗竭，但这可以由下一次种植来逆转。 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. 自然存在于身体中的细胞，仍可能潜在地激活端粒酶或ALT，但它们将被加工了的细胞所稀释而逐渐地被排除，它们也可以被强行“清除”，方法是用同源重组的基因疗法（引进相关基因在原位的无义突变），和／或用化学疗法使加工了的干细胞有抗性。（在更新较缓慢的组织中，似应首选同源重组，因其干细胞不需要种植。）因此，一个人的癌症风险实际上将随龄降低。 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? - 如果癌症不能维持它们的端粒，那么在杀死我们之前它们总要退化吗？ - 端粒维持可以由足够有效地（或选择性地）更易控制的途径而有效地被排除吗？ - 端粒酶或ALT二者都能被排除而对不依赖于端粒长度的细胞或组织无不良效应吗？ －ALT＋是一种简单的丧失功能的突变吗？（在这样的突变中，要掌控非激活性可能较为困难）（译注：作者认为ALT只是一个平时关闭的基因被打开。） － 所有的干细胞库都足够容易重新群体化吗？骨髓似乎很简单，它是这样的吗？肠、皮肤、肺，等又怎样？ - Can we
rely on telomere-depleted stem cells removing themselves by differentiation?
If not, what strategies are appropriate to prevent deleterious side-effects? － 我们能依赖端粒删节的干细胞以分化作用而除去它们自己吗？如果不能，什么策略适于预防有害的副效应？ － 是什么影响DC发作的年龄？它可以在遗传上进行调节吗？与野生型相比，什么是DC中端粒延长的典型速率？ － 人类端粒可以造得多长而仍然起作用？当端粒很长时，它们的磨损速率将像我们在端粒酶负鼠细胞中所看到的那样慢吗？若不，如何能使它减速到那样的速率？ 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 list of participants was: 为了尽可能智慧地探讨这一广泛范围的主题，这次圆桌会议的参与者由所有有关领域的前沿专家组成。以下为参与者一览表：
Nicola Royle： ALT（端粒替代性加长） |
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