Anderson N Leigh, Anderson Norman G
Plasma Proteome Institute, Washington, DC 20009-3450, USA.
Mol Cell Proteomics. 2002 Nov;1(11):845-67. doi: 10.1074/mcp.r200007-mcp200.
The human plasma proteome holds the promise of a revolution in disease diagnosis and therapeutic monitoring provided that major challenges in proteomics and related disciplines can be addressed. Plasma is not only the primary clinical specimen but also represents the largest and deepest version of the human proteome present in any sample: in addition to the classical "plasma proteins," it contains all tissue proteins (as leakage markers) plus very numerous distinct immunoglobulin sequences, and it has an extraordinary dynamic range in that more than 10 orders of magnitude in concentration separate albumin and the rarest proteins now measured clinically. Although the restricted dynamic range of conventional proteomic technology (two-dimensional gels and mass spectrometry) has limited its contribution to the list of 289 proteins (tabulated here) that have been reported in plasma to date, very recent advances in multidimensional survey techniques promise at least double this number in the near future. Abundant scientific evidence, from proteomics and other disciplines, suggests that among these are proteins whose abundances and structures change in ways indicative of many, if not most, human diseases. Nevertheless, only a handful of proteins are currently used in routine clinical diagnosis, and the rate of introduction of new protein tests approved by the United States Food and Drug Administration (FDA) has paradoxically declined over the last decade to less than one new protein diagnostic marker per year. We speculate on the reasons behind this large discrepancy between the expectations arising from proteomics and the realities of clinical diagnostics and suggest approaches by which protein-disease associations may be more effectively translated into diagnostic tools in the future.
如果蛋白质组学及相关学科中的重大挑战能够得到解决，那么人类血浆蛋白质组有望在疾病诊断和治疗监测方面引发一场革命。血浆不仅是主要的临床样本，而且代表了存在于任何样本中的人类蛋白质组的最大和最深层次版本：除了经典的“血浆蛋白”外，它还包含所有组织蛋白（作为渗漏标志物）以及大量不同的免疫球蛋白序列，并且其动态范围非常大，因为白蛋白和目前临床上检测到的最罕见蛋白质之间的浓度相差超过10个数量级。尽管传统蛋白质组学技术（二维凝胶和质谱）有限的动态范围限制了其对迄今已报道的血浆中289种蛋白质（此处列表）的贡献，但多维检测技术的最新进展有望在不久的将来至少使这个数字翻倍。来自蛋白质组学和其他学科的大量科学证据表明，其中一些蛋白质的丰度和结构变化方式表明了许多（如果不是大多数）人类疾病。然而，目前只有少数蛋白质用于常规临床诊断，而且在过去十年中，美国食品药品监督管理局（FDA）批准的新蛋白质检测方法的引入速度却反常地下降到每年不到一种新的蛋白质诊断标志物。我们推测了蛋白质组学预期与临床诊断现实之间存在这种巨大差异的原因，并提出了一些方法，通过这些方法蛋白质与疾病的关联在未来可能会更有效地转化为诊断工具。
