科学家将发起人类蛋白质组计划

日前，一组科学家正在积极筹备发起一个雄心勃勃的研究项目——人类蛋白质组计划（Human Proteome Project），旨在归类和描绘出人体内的所有蛋白质。如果能够实现，这将是继“人类基因组计划”后又一宏伟壮举。该项目预计耗资10亿美元，有研究人员因此质疑组织者能否筹集到如此巨额资金及是否能够调动起相关参与者的研究动力。4月24日出版的《自然》（Nature）杂志也就此发表了社论。

早在20世纪90年代中期人类基因组计划成形时，研究人员就曾考虑过人类蛋白质组计划，但一直没能实现。其中一个重要的原因是，蛋白质组的规模和复杂性令人望而却步。此次项目发起人之一、人类蛋白质组组织（HUPO）前主席John Bergeron说：“过去人们认为这超过了我们的理解能力。”

项目参与者表示，人类蛋白质组计划现在变得可行的部分原因在于，蛋白质编码基因的估计数量大大减少了。过去预测的数量是5万到10万个，而现在认为大约只有2.1万个，这使得人类蛋白质组的规模变得更容易处理。而且项目小组计划聚焦于每个基因产生的单个蛋白质，而不是它的许多种形式。Bergeron说：“我们将去除所有这些复杂性。”

这一项目的目标是，揭示每种组织内的蛋白质种类、弄清每种蛋白质在细胞中的位置以及它们与哪些其它蛋白相互作用。支持者表示，这种蛋白质“目录”对于揭示新药靶和生物标记以追踪疾病进程来说是无价的。项目协作者、瑞典皇家理工学院的Mathias Uhlen说：“想一想描绘生命‘积木’的重要性，那么这一代价就完全是小意思。”

目前，已经建立了两个初步的工作室以讨论这一计划，项目小组准备在将于今年8月举行的人类蛋白质组组织世界大会上首次与更广泛的蛋白质组学界进行商谈。

美国纪念斯隆－凯特琳癌症中心的蛋白质组学专家Paul Tempst认为，“这对人类蛋白质组组织来说是项宏大的事业，之前从没有过。”虽然人类蛋白质组织曾进行过一些大规模的蛋白质组研究，比如人类血浆、肝脏及脑蛋白质组计划，但是这些研究的结果显示，不同的实验室（甚至相同的实验室）经常会从同样的样品中鉴别出非常不同的蛋白质。Tempst说：“这说明了人体中蛋白质数量众多，如果你在不同的实验室进行研究而没有统一的技术标准的话，将会得到不同的结果。”

当然，这一项目面临诸多困难。比如合作的问题，与人类基因组计划相比，人类蛋白质组计划将包括更多的实验室，不可避免地将会遇到数据分享和竞争的问题。

另外，筹集资金也将是个大问题，尤其是在当前科学研究投资紧缩的大环境下。美国国立癌症研究所的Sudhir Srivastava说：“这将是个艰难的‘售卖’。”他给项目组出的主意是，将研究更多地侧重于癌症等疾病方面。他说：“在上马一个宏大项目前，你应该说明它的临床有用性。”

The big ome
It's time to make the case for proteins.

'The body's building blocks', 'cellular machinery': proteins are sometimes stuck with rather mundane labels. Certainly they sit in the scientific shadow of the genome sequence and the eulogies that inspires. So protein biologists face an uphill battle if they are to fire up the research community — and the world beyond — enough to buy into a Human Proteome Project.

The project is just getting past the back-of-the-envelope stage but, in essence, it would systematically catalogue all the proteins manufactured in the body: what they are, where they are and in what abundance (see page 920). A cancer biologist might reveal whether a rogue protein is overexpressed in the tumours she studies compared with levels from healthy tissue that are logged in the proteome register. A geneticist who traces Alzheimer's susceptibility to a region of code could consult the proteome to reveal which proteins are being manufactured from that region in the brain. We can expect this catalogue of proteins to eventually include the targets for almost all future drugs.

There are many obvious parallels with efforts to elucidate the human genome. A human proteome would be a very expensive and ambitious undertaking and, by its nature, the full benefits cannot be spelt out beforehand. That's how it should be. The fun of the human genome is that spelling out the letters did little to decipher the code — there is so much more complexity than had ever been imagined. We can expect that the proteome will also reveal unexpected delights about the ways in which proteins rally together to perform a task or become tissue.

And yet there was a certain intellectual allure about 'cracking' the human genome that, on the face of it, is lacking from cataloguing all the proteins. And although the human genome is finite, the proteome is almost boundless, because each of the body's proteins may be present in different forms and different amounts in each tissue — and even in precisely the same cell from one moment to the next. That very complexity, however, should inspire, not dissuade.

Proteomic analyses have also been viewed with some scepticism, in part because many studies involving mass-spectrometry profiling have proved difficult to reproduce. And the field has so far largely failed to deliver the disease-tracking biomarkers on which these early efforts were sold. There are few examples of clear, clinically proven benefits. Starting out with this kind of reputation will make a Human Proteome Project particularly hard to sell.

The Human Proteome Organisation (HUPO) has taken some praiseworthy steps towards resolving these issues with, for example, a project to show that different labs can now produce identical results from the same sample. With the rapid evolution of proteomic techniques, the field's reputation and utility is likely to pick up. But HUPO — and the proteomics community — still has a lot to prove and a successful Human Proteome Project is its chance to prove it. It needs to consult widely to devise a strategy that has strong community backing. It will also need to demonstrate that the knowledge stemming from this project will transform the research landscape in the same way that the genome sequence has done.

Failing these, either the project will die or HUPO could risk being left on the sidelines as organizations with money to spend make the decisions about how proteomics should be done.

Times have changed since the Human Genome Project — proposals for mega-biology projects are rather more common and money scarcer. HUPO, and all biologists who love proteins, should articulate clearly and loudly the benefits of sinking US$1 billion into protein biology. It will take much work to get due recognition for the 'cell's work-horses'.