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Outline proposal for an Institute of Biomedical
Gerontology 对于生物医学老年学研究所的 简要建议 The most efficient approach to developing ENS will be by a coordinated "Manhattan Project" in which substantial funds are targeted appropriately and systematically. This may be best achieved by setting up a research institute in which much of the work would be done. This page summarises my current vision of how such an institute would work, why it is the best use of a billion dollars, and what main projects it would oversee. 发展ENS的最有效途径是参照"曼哈顿计划"，充实的资助适当地、系统地有的放矢。要最好地做到这一点，可能是建立一个研究所，在研究所中进行大量研究工作。这个网页简述我最近的看法：这样的研究所怎样工作、为何它是利用亿万资金的最好方法、它将督导什么项目。 I have tried to
write it in a form that could be shown to people who might be interested in
providing such capital (or a substantial proportion of it) over ten years. If
you know such a person, please show it to them! 我已经尝试以可以显示给这些人的形式写出：这些人有可能提供资金（或大部分资金）达10年以上。如果您知道这样的人，请把它给他们看。 This page as a Microsoft
Word document 这一个网页是微软Word文件 摘要 什么科学将被资助？ 消除线粒体突变 降解细胞内垃圾 防治癌症 除去多余的、有毒的细胞 破坏细胞外交联键 它将需要多长时间？ 它对小鼠能很好地起作用吗？ 没有IBG它能进行吗？ 它能在人类中加速成功吗？ 为什么你的同事不说同样的话？ 参考文献 Summary 摘要 This memorandum
briefly outlines the case for the setting-up of an Institute of Biomedical
Gerontology (hereafter "IBG"), whose remit would be to promote,
co-ordinate and fund a range of projects leading, jointly, to a genuine cure
for human aging. The memorandum is in two parts. In the first section I
provide answers to the following key questions: 这份备忘录简述了建立一个研究所的例子：建立一个生物医学老年学研究所（以后简称"IBG "），它的组合（remit）将会启动、协同和资助一系列项目，一起导向人类老化的真正治愈。这个备忘录分为两个部分。第一部分是我对以下关键问题提供答案： What main
projects, at what funding level, would IBG support? IBG将以何种资助额度支持什么主要项目？ Why are these
projects likely to succeed within about 10 years? 为什么这些项目在大约10年内能够取得成功？ Why are these
projects likely to confer robust mouse rejuvenation? 为什么这些项目能使小鼠健壮返老还童？ Why is robust
mouse rejuvenation in 10 years unlikely without IBG? 为什么没有IBG，不能在10年内使小鼠健壮返老还童？ Why is robust
mouse rejuvenation the quickest route to curing human aging? 为什么小鼠健壮返老还童是治愈人类老化的最快路线？ Why are most
biologists of aging not saying all this? 为什么大部分衰老生物学家不谈这些？ The second
section discusses in greater detail the projects listed in answer to question
1 above, including their current status, major strands of ongoing research,
milestones realistically achievable in the first few years of funding, and
approximate funding needs. 第二部分详细讨论回答第一个问题所列举的项目，包括它们的现状、正在研究的主要组成部分、在资助的前几年实际可达到的里程碑、大约需要资助多少。 A. Answers to
key questions A．关键问题的答案 What main
projects, at what funding level, would IBG support? - have a
well-defined endpoint of reversing some presently irreversible aspect of
human aging in a mouse model; -do not depend
on any dramatic technological breakthroughs; -are not being
adequately funded by other routes; and - have already
been the subject of exploratory or closely related work. -已经是探索性的或密切相关工作的课题。 -Funding would
be allocated by a peer-review process. Initially, the following topics would
be the subject of calls for applications: b) Enhancement
of lysosomal catabolic versatility with non-mammalian hydrolytic enzymes, so
removing undegradable aggregates (de Grey 2002) e)破坏细胞外蛋白-蛋白交联键，从而恢复基质生物物理特性（主要是弹性） Of these, the
first three have been the subject of publications by Dr. de Grey (de Grey
2000, 2002; de Grey et al 2004). Each of them would require total funding in
the range of $2m to $15m per year, spread over at least three and sometimes
~15 research teams. 其中前三项是Dr. de Grey的文章 (de Grey 2000, 2002; de Grey et al 2004)的主题。每一项需要每年总资助200万美元到1,500万美元，至少分给3个、有时15个研究团队。 These teams
might be working in a physical IBG or in a university or other research
setting. Applications would also be accepted for projects that are not
included within these themes if a sufficiently compelling case can be made
that they meet the four criteria listed above. 这些团队可能正在已有的IBG或大学或其他研究机构工作。对于未被包括在这些题目之内的项目，如果是十分引人注目的例子（符合上述列举的4个标准），其申请也应接受。 Further, IBG
would contribute funds to the Methuselah Mouse Prize, a prize for the
creation of unprecedentedly long-lived mice. The purpose of this prize is to
encourage creativity in the exploration of novel ideas for mammalian
life-extension that are insufficiently concrete to justify direct funding
from IBG. An appropriate level of funding for this prize would be $10m, which
translates to an expected outlay of under $3m/year. Administration of the
prize would cost at most $0.5m per year. 再者，IBG还要捐赠资金给高寿鼠奖，这个奖金是奖励给创造空前长寿小鼠的。该奖金的目的是鼓励创造性：探索对于哺乳动物生命扩展的新颖思维，从IBG来说，它还不够具体证明直接资助是恰当的。对于该奖金的适当级别的资助要1,000万美元，它转换成预期费用低于每年300万美元。该奖金的管理，每年最多耗费50万美元。 Finally, IBG would organise and sponsor conferences dedicated to the field of biomedical gerontology. These would include focused, invitation-only roundtable workshops with only ten or so participants, standard academic meetings covering the broad range of the field, and public meetings designed to communicate IBG's work to the layman. Total outlay on such meetings would be at most $0.5m per year. 最后，IBG还要组织和主办生物医学老年学领域专题研讨会。这些包括若干受关注的、特邀的、10人左右参加的圆桌专题讨论会，要有涵盖各领域的权威学术会议，也有旨在将IBG的工作与外行沟通的公众会议。这样的会议，全部费用最多每年50万美元。 2) Why are these
projects likely to succeed within about 10 years? 2)为什么这些项目有可能在大约10年之内成功？ This expected timeframe derives directly from the criteria listed in the last section. With (a) a substantial body of groundwork and (b) a defined plan of action that has no clearly severe obstacles, the only things that can stretch such a timeframe are unavailability of funds, unavailability of experts interested in doing the work, or unforeseen technical hurdles. The existence of IBG and of applicants for its funds would remove the first two possibilities; the third can never be ruled out entirely, but is made unlikely by the fact that specialists have been sufficiently confident to make the investment in groundwork. 这种所期待的生命框架直接得自上一部分所列举的标准。以(a)坚实的基础工作，和以 (b)的无明显严重障碍的、策划周详的行动计划，可以伸展这样一种时间框架的唯一事情是经费没有着落、兴趣做这项工作的专家没有着落，或无法预料的技术栅篱。有IBG和申请者们有其资助，这将排除前两个可能性；第三点不能完全排除，但是，可以使它成为不可能，就是专家们全身心投入于于基础研究工作中。 Since all these projects already have the detailed structure typical of a commercial R&D project (and atypical of a basic science topic), interim milestones and timelines can readily be specified down to the level of annual or biennial subgoals. IBG would typically commit to a basal level of funding of a given project for at least five years up-front, but this would be subject to large supplementation (typically doubling of an annual budget) on successful achievement of specified milestones. This would provide the correct balance between security (so that high risk but aggressive approaches to the given problem can be pursued) and incentive to achieve progress as speedily as possible. 既然所有这些项目已经具有为商业性研究与开发所特有（和为基础科学题目所非特有）的详细结构，那么中间的里程碑与时间线就很容易定到一年或两年的子目标。IBG 可以典型地定下一个特定项目至少为5年期，而只给予基本的经费额度，但是，为成功达到特定里程碑，它可能会有很大的追加（典型情况下每年预算加倍）。这将提供安全（这样可以提供追踪高风险但又富有进取的特定问题的途径）和激励（尽快取得进展）之间恰当平衡。 3) Why are these
projects likely to confer robust mouse rejuvenation? 3)为什么这些项目可以赋予小鼠健壮返老还童？ First we must define "robust mouse
rejuvenation". For present purposes it will be defined as a treatment
applied to a mouse only after it has reached 75% of its life expectancy, and
which increases its totalremaining healthy
life expectancy.) Also, the mouse must be of a strain whose life expectancy
(in the absence of any treatment) is at least three years (which is long for
a mouse). 首先，我们必须给"小鼠健壮返老还童"下定义。目前，它将被定义为：它是只应用于治疗生命期望值已达到75%之后的小鼠，治疗后的小鼠增加了全部剩下的健康生命期望值。再者，该小鼠必须是纯系的，它的无任何治疗的寿命期望值至少3年（这对小鼠来说是很长的）。 These projects are likely to confer robust mouse rejuvenation because, jointly with a handful of other research areas that are already being well funded by other means, they reverse all the major deleterious molecular and cellular differences between a middle-aged adult and a young adult. 这些项目可赋予小鼠健壮返老还童，因为连同其他一些研究领域（已通过其他途径获得足够资助），他们逆转了中、青年之间所有主要有害分子和细胞的差别。 Dr. de Grey has published detailed analyses of this question both in concert with eminent senior biologists of aging (de Grey et al. 2002a, 2002b) and alone (de Grey 2003). Briefly, there are only seven categories of such change that are not already amenable to effective medical intervention; five of these are addressed by the projects listed earlier and discussed in the second section of this memorandum, and the other two (cell loss and accumulation of extracellular aggregates) are being pursued by relatively well-funded groups. Dr. de Grey已发表了这一问题的详细分析，有的是与著名资深衰老生物学家合作，(de Grey et al. 2002a, 2002b)，有的是单独发表的(de Grey 2003)。简单地说，只有七类这样的变化，它们不接受有效的医学干预；七类中的五类已由早先列举的项目提出，并在这份备忘录的第二部分讨论过，另外两类（细胞丧失和细胞外聚集物积累）由经费较充足的课题组研究。 All aspects of age-related decline are the eventual result of one or more of these changes, so if they were all reversed (either periodically or continuously) and thus did not accumulate with time, aging as we now know it would not occur. It would eventually (at an older age) re-emerge as a result of slower accumulation of other changes that do not cause pathology in what we now consider a normal lifetime; it will be possible to address such changes only when they can be identified, due to having been unmasked by the removal of the changes we already know about. 关龄降低的所有方面最终都是这些变化的一个或一个以上引起的，因此，如果它们都周期性地或连续地被逆转、因而没有随时间积累的话，那么像现在我们所知道的老化就不会发生。它将最终（在较老年龄）因不引起病理学的、我们现在称之为正常寿命的其他变化的较缓慢积累而重新出现；由于我们已经知道的变化被除去而暴露出来，因此只有当它们能被鉴定出来时才能够指出这样的变化。 However, the degree of life extension defined as "robust mouse rejuvenation" above will be achieved without solving such "second-generation" problems. 然而，上述定义为"小鼠健壮返老还童"生命扩展的程度将被达成而没有解决这样的"第二世代"问题。 4) Why is robust
mouse rejuvenation in 10 years unlikely without IBG? 4)为什么没有IBG不可能在10年中实现小鼠健壮返老还童？ At present, no organisation is supporting work of the sort described above, except where it can be packaged as having applications outside life extension. 目前，没有一个机构正在支持上述的这类研究，除了这类研究可以被包装为在生命扩展之外有其应用。 Moreover, when such funding is available it is always targeted at the most modest, short-term projects and/or those with a "basic science" purpose, i.e. directed at improving our understanding of some aspect of biology as opposed to our manipulation of it. 再者，当有了这样的资助时，它的目标总是指向最有节制的短期项目和／或指向那些具有"基础科学"目的的项目，即指向改善我们理解某些生物学方面（这与我们操作它相反）。 At the opposite
end of the spectrum is work on what we now think of as "anti- aging
medicine", namely supplements and other interventions aimed at a very
modest extension of life expectancy. The projects on which IBG would focus
fall between these two stools: too ambitious-sounding to be medically
respectable but too goal-directed to be biologically respectable. 在这个光谱的相反一端，是我们现在视为"抗老化医学"的研究，即目标针对生命期望值很有限扩展的添加和其他干预。IBG所关注的项目两头落空：雄心太大在医学上很难得到尊重，而目标过于明确在生物学上难被接受。 Thus, without a
source of funding whose specific remit is to fill this vacuum, this work is
likely to be delayed by up to a decade. That translates into a prediction of
roughly half a billion people dying of old age without IBG but not if it were
set up now. Moreover, IBG would, as principal funder of all these projects, be in a strong position to facilitate and accelerate their co-operation and thus the rapid generation of mice benefiting from all projects. This is much less likely to occur in traditional funding environments. 没有资助来源（资助来源的特别的一组工作是填补这一真空），这项研究工作很可能被搁置10年。这可化为一个粗略的预期值：5亿老年人因无IBG而死亡，但是，如果IBG现在就建立，那就不会。 再者，IBG作为所有这些项目的主要资助者，它将处于强有力的地位：能帮助和促进各项目之间的合作，这样，能迅速产生受益于各个项目的（高寿）小鼠。这在传统资助环境中是不大可能发生的。 5) Why is robust
mouse rejuvenation the quickest route to curing human aging? 5)为什么小鼠健壮返老还童是治愈人类老化的最快途径？ The reason is a combination of science
and sociology. The later stages of developing a true cure for human aging
will be funded publicly, as a result of a vigorous demand from society to
develop it as soon as possible. That demand will arise only when society
begins to feel that curing human aging is foreseeable, in contrast to the
present situation where virtually everyone considers it totally impossible
within their or their children's lifetimes and thus does not agitate for it. 理由是科学和社会学的综合。开发真正治愈人类老化的后期阶段将由公众资助，因为社会大力要求尽快发展它。只有当社会开始感到治愈人类老化看得见、摸得着时，才会有这种要求，这与现在的情形形成鲜明对比：实际上现在每个人都认为在他们或他们孩子寿限内是完全不可能的，因而对它漠不关心。 Thus, the
quickest route to curing human aging is to achieve results in the lab that
are sufficiently impressive to effect this change in public attitude. Robust
mouse rejuvenation, as defined above, should suffice to do this and is doable more quickly than
any comparably impressive. This is because of the great wealth of knowledge and technical
expertise in mouse manipulation that has been built up over the past century,
together with the mouse's relative similarity to humans (as compared with
fruit flies, for example). 这样，治愈人类老化的最快捷途径，是在实验室中完成给人以深刻印象的成果，以此来改变公众的态度。小鼠健壮返老还童（定义如上）应该足以做到这一点，而且能够比任何同等印象深刻的进展都做得更快。这是因为在小鼠操作中的大量知识和技术在上世纪已经建立了起来，再加上小鼠比较类似于人类（例如，与果蝇比较）。 6) Why are
most biologists of aging not saying all this? 6)为什么大部分衰老生物学家不谈这些？ In a nutshell,
most scientists don't understand engineering. Science is not about
controlling or intervening in a process, but about understanding things as an
end in itself. 简单地说，大多数科学家不懂工程学。科学不是从事控制或干预一个过程，而是了解事情本身始末。 Thus, nearly all biologists of aging stress how complex aging is, but they conclude from this that we must research it in far more detail than we have so far done before we have any hope of designing interventions that will work. The engineer agrees that an inadequate understanding of a system precludes its reliable manipulation, but he also knows that rather incomplete understanding may be enough. To take an extreme example, one doesn't need to know much of the detail of how a horse works in order to get it to carry one where one wants. 因此，几乎所有衰老生物学家都强调衰老是多么复杂，从这一点出发，他们得出结论：在我们有希望设计出能起作用的干预技术之前，我们必须比迄今所做的还要更详细地研究衰老。工程师同意，对一个系统了解不够会妨碍它的可靠操作，但是，工程师也知道，不太完全的了解可能就足够了。举一个极端的例子，要骑一匹马到一个地方，人们不必详细了解马怎样工作。 Conversely,
however, most engineers don't understand science. There is a strong tendency
for engineers initially to underestimate the complexity of a system,
particularly in biology where the system is so extremely complex, and hence
to propose interventions that will not work because they overlook some aspect
of the problem. 然而，相反地，大多数工程师不了解科学。工程师们有一个强烈倾向：开始时低估了一个系统的复杂性（特别是生物学系统极端复杂），因此提出了不起作用的干预法，因为他们没看清问题的某些方面。 I am a
biologist of aging with a background in computer science. Hence I am in an
unusually good position to avoid either of the above errors, because I have a
thorough knowledge of the nature of mammalian (including human) aging and
also a goal-directed way of thinking that promotes the identification of
feasible interventions which are likely to work. 我是一名具有计算机科学背景的衰老生物学家。因此，我处于能避免上述两种错误的极好位置，因为我完全知道哺乳动物（包括人类）老化的本质，也有目标明确的思维方式：它能启动识别出可以起作用的、可行的干预技术。 There are
also other reasons for the pessimism of most biogerontologists’ public
remarks about the likely rate of progress, which are perhaps easier to
understand because they apply in many professions, not just science. 也有其他悲观的理由：大多数生物老年学家告诉公众所谓进展的可能速度，这种悲观主义可能更容易理解，因为它们适用于很多专业，不单只适用于科学。 The progress of
ideas always has enormous inertia, on account of the emotional, intellectual
and financial investment that those who hold conventional views have made in
those views. Scientists, like others, find it difficult to write off that
investment and embrace a new paradigm even when the argument for that new
paradigm is very comprehensive. 观念的进步总是有巨大的惯性，由于拥有投资观念的那些人的情感、智力和财政投资已经形成了那些投资观念。科学家与其他人一样，发现很难削弱这样的投资观念而拥抱一种新的模式，即使争辩说这样一种新的模式是多么合理。 This manifests
as a reluctance to consult relevant scientific literature, for example, or
even to entertain the idea that such literature is relevant in the first
place. It also manifests as a preference for avoiding overt debate on such
matters, since any such debate opens up the risk of being forced to
acknowledge the superiority of the new paradigm. None of this is conscious,
but it is an indescribably powerful force against progress. 例如，这表现为不愿咨询相关的科学文献，或甚至在开始时就不愿接受这样的文献相关的观念。它也表现为在这样的事情上喜欢去避免公然的辩论，因为任何这样的辩论都会甘冒被逼承认新模式优越性的风险。这当中没有一个是故意的，但是，它是阻碍进步的巨大力量。 Another aspect
in which I am fortunate is that, since I have no laboratory of my own, my
continued career is not critically dependent on anonymous evaluation of my
work by other biogerontologists (peer review). 我幸运的另一个方面是，因为我没有自己的实验室，所以我的履历并不评判性地取决于我的工作受其他生物老年学家背靠背的评估（同行专家评论）。 This means that
I can be extremely candid in my criticisms of those in my field who are most
egregiously guilty of the above shortcomings, without fear of serious
repercussions. Accordingly, I regularly write quite confrontational
commentaries on such matters in both the academic and wider literature, as a
way to embarrass my colleagues into abandoning their dogma-preserving
silence. This is increasingly succeeding, but there is a long way to go. 这意味着，我可以在我的领域里有着严重上述缺点那些人的评判意见中是极端公正的，无严重反响之虞。因此，我可以在学术文章或科普文章中经常就这样的事情写一些很不同的意见来困惑我的同事们，使他们放弃他们死抱教条的沉默。这一点正在逐渐取得成功，但是还有很长的路要走。 B.
Prospective IBG-targeted projects: status and near-term directions B. IBG瞄准的预期项目：现状和近期趋势 This section briefly outlines the status and next steps of five key strands of translational research that will form components of robust mouse rejuvenation. The motivation for pursuing that goal, and hence these projects, is summarised in the previous section. Funding level estimates are also given, based on an average cost to the funding source of $200,000 per full-time researcher per year including salary, research equipment and supplies. 这一部分简要叙述现状和下一步转换研究的的五个关键组成部分（它们将形成小鼠健壮返老还童的组成部分）。寻求该目标、从而推行这些项目的动机，已被摘要地写进上一部分中。也提出了资助额度评估，根据是：每个全职研究人员平均每年花费20万美元经费来源（包括薪水、设备和供给品）。 a) Functional
introduction of all 13 mitochondrial protein-coding genes into the nucleus,
so making mitochondrial mutations harmless a)所有13种编码线粒体蛋白质的基因功能引入细胞核，这样使得线粒体突变成为无害。 Basis:
mitochondrial mutations accumulate with age, with the result that some cells
become unable to use oxygen. This happens faster in shorter-lived species,
suggesting that it contributes to aging. Only 13 proteins are susceptible to
such mutations; the other 1000 or so proteins in mitochondria are encoded in
nuclear DNA, which is hugely better protected. 原理：线粒体突变是随龄积累的，其结果是某些细胞变得不能利用氧气。在这短寿的物种中发生得更快，提示了它与老化有关。只有这13种蛋白质容易受这样的突变影响；线粒体中的其他1000种左右的蛋白质是在细胞核DNA中编码的，它们非常好地受到保护。 Thus, we should
introduce copies of the 13 genes into the nucleus (by gene therapy in humans,
but first by much more established techniques in mice) so that these 13
proteins are present even if mitochondrial mutations have occurred. This will
mean that cells remain able to use oxygen and therefore healthy and
non-toxic. 这样，我们应当把这13种基因的拷贝引进细胞核（应用人类基因疗法，但是，首先应用小鼠中的建立得多得多的技术），使得这13种基因仍然存在，即使已经发生了线粒体突变。这将意味着，这些细胞仍然可以利用氧气，因此仍然是健康的和没有中毒的。 Origin:
First suggested as an anti-aging therapy by Hoeben in 1993. Usually termed
"allotopic expression". The general concept of introducing
mitochondrial genes into the nucleus was first proposed and implemented (in
yeast) by Nagley's group in 1986. 起因：1993年由Hoeben首先提出作为抗老化疗法。通常称为"异题表达"。把线粒体基因移进细胞核的总概念，于1986年首先由Nagley的课题组提出和进行（在酵母中）。 Status: Three of the 13 proteins have been
expressed from the nucleus and shown to work (allowing oxygen utilisation
when the mitochondrial counterpart was mutant). However, this has only been
done in cell culture so far, not in live mice. 现状：13种蛋白质中的3种已从细胞核表达，并被证明能起作用（当线粒体的对应拷贝发生突变时能利用氧气）。然而，迄今这只在细胞培养中、而不是在活小鼠中进行。 Next steps: Several approaches to making all 13 genes work, first in culture and then in mice, have been proposed, reviewed by (de Grey 2000). A key recent advance has been to clone four of these genes from green algae, which naturally have them in the nucleus; this will allow emulation of the tricks that evolution has found to make them work. 下一步：使全部13种基因都起作用（先在培养中而后在小鼠中）的几种方案已被提出（综述见de Grey 2000）。目前关键的进展是从绿色藻类（green algae）克隆了13种基因中的4种，在自然情况下绿色藻类在细胞核中有这4种基因；这将引起仿效进化曾经发现使它们起作用的诀窍。 However,
several of these genes have never been found in the nucleus of any species,
so this may not solve the whole problem (though it may, because we can apply
a solution that exists for one gene to other genes more easily than evolution
can). Two main alternative approaches exist: modifying the genes with
sequences called "inteins" (see de Grey 2000) and using proteins
that do not pump protons. 然而，这些基因中有几种从未发现于任何物种的细胞核中，这样，可能不能解决全部问题（虽然可能解决，因为我们可以应用一种解决方案，它对于一个基因到许多其他基因存在得比进化可以做到的更容易）。有两个主要的替代方案：一为利用称为"inteins"（见de Grey 2000）的序列来修饰基因，二为利用不泵质子的蛋白质。 Key
investigators: At least a dozen laboratories are currently doing work related
to this problem. Most of them and their relevant work are cited in (de Grey
2000). In all cases, however, the work is proceeding fitfully as a result of
very limited funding. 关键的研究人员：至少有一打的实验室目前正在从事与这个问题有关的研究工作。这类研究的大多数及其相关研究已被列出(de Grey 2000)。然而，在所有情况下，由于资助有限，研究工作都是停停打打的。 The idea of
allotopic expression as a human therapy is relatively long-term (might take
5-10 years to get working in mice), and such projects are not favoured by
traditional funding agencies. This situation has actually become worse in the
past year or two since the initial successes mentioned above, because prior
to that it could be argued that allotopic expression was basic science
(finding out why these proteins are hard to encode in the nucleus) whereas
now it is "only" technology. 异题表达作为一种人类疗法的想法是相对长期性的（可能需要5-10年才能在小鼠中起作用），传统资助机构不喜欢这样的项目。这种情形自从上面所谈到的初战告捷之后，在过去一两年实际上变得更糟糕，因为在那之前，还可以争辩说：异题表达是基础科学（找出为什么这些蛋白质在细胞核中很难编码），而现在它是"纯"技术学问题了。 But this recent
history means that there is abundant appropriate expertise available, which
needs only adequate funding to be remobilised. 但是，这段新近的历史意味着，有很多的合适专门技术可资利用，它只需要合适的资助来重新推动。 Funding level
and priorities: The first task is to make all 13 genes work in cell culture.
There are three major approaches to this that presently seem feasible (see
"Next steps" above), each of which is being pursued by at least one
laboratory, but for each of which several variations exist that would be best
pursued in other labs. 资助额度和优先权：第一个任务是在细胞培养中使所有13种基因起作用。目前有三条途径似乎是可行的（见上述"下一步"），每一条途径至少由一个实验室来实验，但是每一条途径最好有若干子途径在不同实验室中进行实验。 Thus, a
realistic estimate is that a call for applications would receive 8-12
applications that strongly merited funding. Each of these applications would
typically be for two to four full-time researchers for five years, with the
goal of making some or all of the 13 genes work in cell culture. In all
cases, the translation of that success to live mice would be the subject of a
further five-year period of funding at a similar level. Total cost to IBG
would be in the range $5m-$7m per year. 这样，现实评估是，一次征集申请，可得到8-12份很值得资助的申请。每一份申请通常须2-4名专职研究人员工作5年，旨在使某些或全部13种基因在细胞培养中起作用。在所有场合，把成功的成果转换到小鼠是另一个5年期资助的主题（资助标准相似）。IBG的总支出为每年500-700万美元。 Milestones: Manipulation of mitochondrial DNA has recently improved, such that it will very soon be possible to engineer mutations in particular mitochondrial genes while leaving others intact. This will greatly facilitate work on each of the 13 genes in isolation. 里程碑：线粒体DNA的操纵最近已有改善，将会很快就能够操控特殊线粒体基因的突变，而其他线粒体基因仍然保留完整。这将大大推动13种基因的每一种的分离工作。 An initial milestone will be to get each gene working in cells in which it is the only one whose mitochondrial copy is mutant. Some will be easier than others, and we cannot know which technique will work best. Milestones would thus be set on a case-by-case basis, depending on the specifics of the approach being pursued. 开始的里程碑将是使得每一个基因在细胞中起作用：在细胞中它是唯一线粒体拷贝突变的基因。一些基因将比其他基因容易些，我们不可能知道哪项技术将会最好地起作用。因此，里程碑将被在逐个项目相比较的（case-by-case）基础上，取决于该途经被进行的效果。 After a given
gene had been made to work, a key next step would be to make more than one
gene work in the same cell; this may again throw up unexpected problems but
they would be likely to be relatively easy to solve compared with the initial
one-gene problems. By the five year point, a key goal would be to have all 13
genes working in the same cell. 在使一个已知基因能够起作用之后，关键的下一步将是使一个以上的基因在同一个细胞中起作用；这可能再一次抛出意料不到的问题，但是它们可能比较容易解决（同开始时的1-基因问题相比较而言）。到5年即将到期时，关键的目标将是所有13种 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||